Proton-gated Na+-permeable channels are the simplest form of ligand-gated channels. They are present in many neuronal cell types throughout the central nervous system, suggesting an important function of these channels in signal transduction associated with local pH variations during normal neuronal activity. These channels might also play an important role in pathological situations such as brain ischemia or epilepsy which produce significant extracellular acidification. They are also present in nociceptive neurons and are thought to be responsible for the sensation of pain that accompanies tissue acidosis in muscle and cardiac ischemia, corneal injury, and in inflammation and local infection.
It is only very recently that the first proton-gated channel, ASIC (for Acid Sensitive Ion Channel) was cloned (Waldmann, R., Champigny, G., Bassilana, F., Heurteaux, C. and Lazdunski, M. “A Proton-Gated Cation Channel Involved in Acid-Sensing”, Nature, 386, 173–177, 1997.) The ASICs belong to a superfamily which includes amiloride-sensitive epithelial Na+ channels (ENaCs), the FMRFamide-gated Na+ channel (FaNaC) and the nematode degenerins (DEGs), which probably correspond to mechano-sensitive Na+-permeable channels. Several ASIC subunits have now been described: ASIC1a (Waldmann, R., above) and ASIC1b (Chen, C. C., England, S., Akopian, A. N. and Wood, J. N., “a Sensory Neuron-Specific, Proton-Gated Ion Channel”, Proc. Natl. Acad. Sci. USA, 95, 10240–10245, 1998), ASIC2a (Price, M. P., Snyder, P. M. and Welsh, M. J., “Cloning and Expression of a Novel Human Brain Na+ Channel”, J. Biol. Chem., 271, 7879–7882, 1996) and ASIC2b (Lingueglia, E., de Weille, J. R., Bassilana, F., Heurteaux, C., Sakai, H., Waldmann, R. and Lazdunski, M., “a Modulatory Subunit of Acid Sensing Ion Channels in Brain and Dorsal Root Ganglion Cells”, J. Biol. Chem., 272, 29778–29783, 1997), ASIC3 (Waldmann, R., Bassilana, F., de Weille, J., Champigny, G., Heurteaux, C. and Lazdunski, M., “Molecular Cloning of a Non-Inactivating Proton-Gated Na+ Channel Specific for Sensory Neurons”, J. Biol. Chem., 272, 20975–209758, 1997). The different subunits produce channels with different kinetics, external pH sensitivities and tissue distribution. They can form functional homomultimers as well as heteromultimers.
ASIC1a and ASIC1b both mediate rapidly inactivating currents following rapid and modest acidification of the external pH. However, while ASIC1a is present in both brain and afferent sensory neurons, its splice variant ASIC1b, is found only in sensory neurons. ASIC2a forms an active H+-gated channel and is abundant in the brain, but essentially absent in sensory neurons while its splice variant ASIC2b is present in both brain and sensory neurons and is inactive as an homomultimer. ASIC2b can form functional heteromultimers with other ASIC subunits and particularly ASIC3. ASIC3 is found exclusively in small sensory neurons which act as nociceptors. Its expression in various heteromultimeric systems generates a biphasic current with a fast inactivating phase followed by a sustained component. The association of ASIC2b with ASIC3 forms an heteromultimer with properties (time course and ionic selectivity) similar to those of a native sustained H+-sensitive channel which is present in dorsal root ganglion cells and appears to play a particularly important role in pain sensation.
Venoms from snakes, scorpions, sea anemones, marine snails and spiders are rich sources of peptide toxins which have proven of great value in the functional exploration of voltage-sensitive and ligand-gated ion channels (Hucho, F. (1995), “Toxins as tools in neurochemistry”, Ang. Chem. Int. Ed. Eng., 34, 39–50). Nevertheless, there is a continuing need to find new materials which affect these channels.